The specific inhibition of the cardiac electrogenic sodium/bicarbonate cotransporter leads to cardiac hypertrophy.

Two alkalinizing mechanisms coexist in cardiac myocytes to maintain intracellular pH: sodium/bicarbonate cotransporter (electroneutral isoform NBCn1 and electrogenic isoform NBCe1) and sodium/proton exchanger (NHE1). Dysfunction of these transporters has previously been reported to be responsible for the development of cardiovascular diseases. The aim of this study was to evaluate the contribution of the downregulation of the NBCe1 to the development of cardiac hypertrophy. To specifically reduce NBCe1 expression, we cloned shRNA into a cardiotropic adeno-associated vector (AAV9-shNBCe1). After 28 days of being injected with AAV9-shNBCe1, the expression and the activity of NBCe1 in the rat heart were reduced. Strikingly, downregulation of NBCe1 causes significant hypertrophic heart growth, lengthening of the action potential in isolated myocytes, an increase in the duration of the QT interval and an increase in the frequency of Ca2+ waves without any significant changes in Ca2+ transients. An increased compensatory expression of NBCn1 and NHE1 was also observed. We conclude that reduction of NBCe1 is sufficient to induce cardiac hypertrophy and modify the electrical features of the rat heart.

Sarcoidosis and the alpha chemokine MIG.

In patients with sarcoidosis, a lot of researches showed increased levels of the Th1 chemokine monokine induced by interferon (IFN)-γ (MIG) and its (C-X-C motif) receptor (CXCR)3 both in biopsy specimens and bronchoalveolar lavage fluid (BALF). In BALF these levels were associated with CD4(+) and total lymphocytes. Positive CXCR3 ligands staining were found in the alveolar macrophages, and in the epithelioid and giant cells in the sarcoid lungs. It can be assumed that in sarcoid lung the accumulation of Th1 lymphocytes is largely related to MIG. Moreover, the potential role of MIG as a biomarker of sarcoidosis and its severity were proven, given its circulating levels that correlated with the clinical course and gravity of the disease.

The Th1 chemokine MIG in Graves' Disease: a narrative review of the literature.

Type-1 helper (Th1) dependent chemokines, such as monokine induced by interferon (IFN)-γ (MIG) seem to contribute to the Graves' disease (GD) pathogenesis. The thyrocytes secrete the chemokine (C-X-C motif) ligand (CXCL)10 under the IFN-γ influence. Therefore, high levels of MIG in peripheral liquids indicate a Th1 orientated immune response and are associated with the active phase of GD in hyperthyroid patients (newly diagnosed and relapsing). Methimazole (MMI), used for the hyperthyroidism treatment, causes a reduction of the MIG secretion by isolated thyrocytes, a decrease of serum MIG levels and leads to a shift from a Th1 to Th2 response in patients with GD in the active phase. The Th1 lymphocytes recruited in the tissues enhance the IFN-γ and tumor necrosis factor (TNF)-α production, that in turn stimulate MIG secretion from these cells; this mechanism originates an amplification feedback loop, causing a perpetuation of the autoimmune process. It has been seen that peroxisome proliferator-activated receptors (PPAR)-γ and PPAR-α activators can modulate the IFN-γ induced MIG secretion in vitro, in GD thyrocytes. More studies are needed to examine the interactions between cytokines and chemokines in the GD pathogenesis and to evaluate the role of MIG as a new therapeutic target.

Platelets interact with Coxsackieviruses B and have a critical role in the pathogenesis of virus-induced myocarditis.

BACKGROUND: To further understand the role of platelets in the pathogenesis of viral infections we explored platelet interaction with Coxsackieviruses B (CVB) 1 and 3. CVB is a group of viruses that cause the majority of human enterovirus-related viral myocarditis; their receptor (CAR) is expressed on the platelet surface and there is a well-characterized CVB3-induced myocarditis murine model. METHODS: Human platelets were infected with CVB1 and 3 and viruses were detected in pellets and in supernatants. C57BL/6J mice with or without platelet depletion were inoculated with CVB3 and peripheral blood and heart samples collected at different times post-infection. RESULTS: CVB1 and 3 RNA and a capsid protein were detected in infected platelets. Despite the fact that titration assays in Vero cells showed increasing infectivity titers over time, supernatants and pellets from infected platelets showed similar levels, suggesting that platelets were not susceptible to a replicative infectivity cycle. CVB binding was CAR-independent and resulted in P-selectin and phosphatidylserine (PS) exposure. CVB3-infected mice showed a rapid thrombocytopenia that correlated with an increase in platelet PS exposure and platelet-leukocyte aggregates without modification of platelet P-selectin expression or von Willebrand factor levels. Mortality, viremia, heart viral titers and myocarditis were significantly higher in platelet-depleted than normal animals. Type I IFN levels were not changed but IgG levels were lower in infected and platelet-depleted mice. CONCLUSIONS: Our data reveal that platelets play a critical role in host survival and immune response against CVB3 infection.

A novel index for predicting macular thickening after cataract surgery.

PURPOSE: In this study, we tried to investigate weather or not the preoperative anterior chamber depth, the lens thickness (LT) and the relation between these variables by the ratio (K) of the distance from the corneal peak to the posterior side of the lens (A) (K = A/LT) could be predictive for a surgically induced foveal thickening following uneventful cataract surgery in normal, emmetropic eyes. PATIENTS AND METHODS: A total amount of 45 eyes, 25 females and 20 males, were enrolled in this study and underwent uncomplicated phacoemulsification under topical anesthesia. A complete ophthalmological examination was performed preoperatively, including refraction, best corrected visual acuity, slit-lamp examination, biometry and optical coherence tomography of both eyes. These examinations, with the exception of the biometric examination, were repeated one day, one week and four weeks after surgery. RESULTS: The K ratio was positively correlated with the macular thickness changes after cataract surgery. The Pearson correlation analysis of K ratio and foveal thickness changes was 0.792 (y = 36.457x - 52.558, R2 = 0.6266). CONCLUSIONS: A novel ratio that incorporates preoperative ocular parameters has been described. It could be easily measured in a clinical setting, and appears to be strongly predictive for macular thickening following cataract surgery. Of course, further studies enrolling a larger amount of patients are necessary in order to confirm these preliminary data.

Changes in vital signs during cataract phacoemulsification by using peribulbar or topical anesthesia.

AIMS: To compare changes in vital signs and pain level experienced by patients during phacoemulsification and foldable intraocular lens (IOL) implantation using either topical/intracameral or peribulbar anesthesia. MATERIALS AND METHODS: In this prospective, parallel-group clinical study 46 consecutive patients (mean age 72.9 +/- 8.1 years) undergoing cataract surgery were randomized to receive topical/intracameral (group1) or peribulbar (group 2) anesthesia. Systolic, diastolic and mean blood pressures, hearth rate, oxygen saturation and pain level were recorded before and during the anesthesiological procedure and thereafter during each surgical step. RESULTS: Diastolic blood pressure during phacoemulsification and after surgery as well as mean arterial pressure after surgery were significantly higher in group 1 compared to group 2. Variability of systolic and mean arterial pressures across the study phases was significantly higher in group 2 compared to group 1. A significantly higher percentage of patients in group 2 compared to group 1 (35.3% vs 3.4%, p=0.007) showed a heart rate reduction greater than 10% from the anesthesiological to the following surgical phase. Higher incidence of moderate pain in group 2 was reported during the anesthesiological procedure (64.7% vs 3.4%, p<0.00001) while higher incidence of moderate pain was reported in group 1 during phacoemulsification (31% vs 5.9%, p=0.047) and IOL implantation (21.7% vs 2.2%, p=0.02). DISCUSSION: Our short study seems to recommend the use of topical/ intracameral anesthesia for cataract surgery due to more stable heart rate, diastolic and mean blood pressures. However, further studies enrolling a higher amount of patients are necessary to confirm our preliminary data.

Optical devices in highly myopic eyes with low vision: a prospective study.

AIMS: To compare, in relation to the cause of visual impairment, the possibility of rehabilitation, the corrective systems already in use and the finally prescribed optical devices in highly myopic patients with low vision. Some considerations about the rehabilitation of these subjects, especially in relation to their different pathologies, have also been made. MATERIALS AND METHODS: 25 highly myopic subjects were enrolled. We evaluated both visual acuity and retinal sensitivity by Scanning Laser Ophthalmoscope (SLO) microperimetry. RESULTS: 20 patients (80%) were rehabilitated by means of monocular optical devices while five patients (20%) were rehabilitated binocularly. We found a good correlation between visual acuity and retinal sensitivity only when the macular pathology did not induce large areas of chorioretinal atrophy that cause lack of stabilization of the preferential retinal locus. In fact, the best results in reading and performing daily visual tasks were obtained by maximizing the residual vision in patients with retinal sensitivity greater than 10 dB. A well circumscribed area of absolute scotoma with a defined new retinal fixation locus could be considered as a positive predictive factor for the final rehabilitation process. DISCUSSION: A more careful evaluation of visual acuity, retinal sensitivity and preferential fixation locus is necessary in order to prescribe the best optical devices to patients with low vision, thus reducing the impact of the disability on their daily life.

Early lamellar macular hole in Alport syndrome: case report and review of the literature.

PURPOSE AND METHOD: To present a 26-year-old Italian woman affected by genetically ascertained Alport syndrome. The patient underwent a complete ophthalmological examination including: visual acuity, anterior and posterior segment biomicroscopy, MP1-microperimetry, colour fundus retinography, electrofunctional examinations (electrooculogram, electroretinogram, visually evoked potentials), computerized perimetry and Spectral Domain Optical Cohrence Tomography. RESULTS AND CONCLUSIONS: Nephritis, haematuria but no hearing impairment was observed. Visual function was normal, also confirmed by electrofunctional tests and computerized perimetry. The ocular involvement was only expressed by an early lamellar macular hole characterized by a density rarefaction in the tomographic images of both inner retina and superficial choroid. A rarefaction of the inner choroid in the whole macular region and in the peripapillary area, unusual for the young age of the patient, was also evident. We suppose that these tomographic findings might be caused by alterations of type IV collagen, typical of Alport syndrome.

Expression and functionality of type I interferon receptor in the megakaryocytic lineage.

BACKGROUND: Type I interferons (IFN-I) negatively regulate megakaryo/thrombopoiesis. However, expression of the IFN-I receptor (IFNAR) in the megakaryocytic lineage is poorly characterized. OBJECTIVES: To study the expression and functionality of IFNAR in the megakaryocytic lineage. METHODS AND RESULTS: Although IFNAR mRNA was found in every cell type studied, its protein expression showed differences between them. According to flow cytometry and immunofluorescence, IFNAR1 was observed in Meg-01, Dami, CD34+ cells and megakaryocytes, but not in proplatelets or platelets. Immunoblotting assays showed that IFNAR1 and IFNAR2 were highly expressed in all cell types, except in platelets where it was barely detectable. Regarding IFNAR1, 130- and 90-kDa bands were detected in Meg-01 and Dami, whereas 130- and 60-kDa bands were found in CD34+ cells and megakaryocytes. Activation of megakaryocytic IFNAR by IFN-ß induced pSTAT1/2 and upregulated the antiviral genes IRF7 and MXA. The latter response was completely suppressed by IFNAR blockade. In contrast, the low levels of IFNAR in platelets were not functional as pSTAT1/2, aggregation and P-selectin expression were not induced by IFN-I. In addition, megakaryocytes increased IFN-I transcript levels and produced IFN-ß upon stimulation with PolyI:C, a synthetic dsRNA that mimics viral infection. CONCLUSIONS: Early progenitors and mature megakaryocytes, but not platelets, express functional IFNAR and synthetize/release IFN-ß, revealing not only that megakaryo/thrombopoiesis regulation by IFN-I is associated with a specific interaction with its receptor, but also that megakaryocytes may play a role in the antiviral defense by being both IFN producers and responders.

Relativistic descriptions of final-state interactions in charged-current quasielastic neutrino-nucleus scattering at MiniBooNE kinematics.

The results of two relativistic models with different descriptions of the final-state interactions are compared with the MiniBooNE data of charged-current quasielastic cross sections. The relativistic mean field model uses the same potential for the bound and ejected nucleon wave functions. In the relativistic Green's function model, the final-state interactions are described in the inclusive scattering consistently with the exclusive scattering using the same complex optical potential. The relativistic Green's function results describe the experimental data for total cross sections without the need to modify the nucleon axial mass.

Spontaneous closure of bilateral full thickness macular holes without surgery: an eleven-year follow-up.

PURPOSE AND METHOD: To present a 60-year-old woman affected by bilateral full thickness macular hole, showing without surgery a spontaneous resolution of the disease in both eyes that remains unchanged during an eleven-year follow-up. To our knowledge, this clinical case is uncommon as no similar reports with such a long follow-up have been published in the scientific literature at this time. RESULTS AND CONCLUSIONS: A spontaneous and bilateral closure of full thickness macular holes was detected, as a consequence of a complete posterior vitreous detachment documented by optical coherence tomography images. An initial reduction up to a complete resolution of the central macular scotoma was also observed by performing scanning laser ophthalmoscope microperimetry. Both these anatomical and functional results did not change during the whole period of follow-up. According to this study, the release or the weakening of the vitreous tractions at the foveal edges seems to play a key role in the spontaneous resolution of macular holes in not surgically treated patients.

Bilateral non-arteritic anterior ischemic optic neuropathy (NA-AION): case report and review of the literature.

PURPOSE/METHOD: To present a 72-year-old woman affected by non-arteritic anterior ischemic optic neuropathy (NA-AION). To our knowledge, this clinical case, showing a bilateral form of NA-AION, is uncommon as only very few similar reports have been published in the scientific literature at this time. RESULTS/CONCLUSIONS: Visual acuity was reduced to 6/20 in both eyes, color vision was absent and computerized perimetry showed an absolute and general reduction of the retinal sensibility within 30 degrees around the fixation point. Pattern visual evoked potentials and pattern electroretinograms showed normal morphologies but delayed latencies and reduced amplitudes. An updated review of the literature has also been done.

Advances in biochemical mechanisms of diabetic retinopathy.

Diabetes mellitus is a major cause of blindness in the working population of the Western World. Numerous large, prospective, randomized clinical trials have delineated the current standard prevention and treatment protocols including intensive glycemic and blood pressure control as well as laser photocoagulation for clinically significant macular edema and/or proliferative retinopathy at a high risk for tractional retinal detachment. However, despite all these interventions, vision loss from diabetic retinopathy still occurs at an alarming rate and no data provide an adequate explanation for the serious and rapid involvement of the retinal microcirculation that may be observed in the disease despite a good metabolic control. In fact, there is now ample of evidence that the development of diabetic retinopathy is a multifactorial process where genetic, metabolic and growth factors play an important role. Some biochemical mechanisms, supposed to be involved in the pathogenesis of diabetic retinopathy, have been highlighted in this review.

Determination of TGFbeta1 protein level in human primary breast cancers and its relationship with survival.

Transforming growth factor-beta (TGFbeta)1 is thought to be implicated in breast cancer progression. However, data about the influence of TGFbeta1 on breast cancer development are conflicting. To clarify the clinical relevance of TGFbeta1, TGFbeta1 protein level has been measured by enzyme-immunoassay in 193 breast tumour samples. We found that 94.3% of patients expressed TGFbeta1 with a range of 0-684 pg mg(-1) protein. In the overall population, an increase of tumoral TGFbeta1 was observed in premenopausal patients when compared to postmenopausal subgroup (P=0.0006). When patients were subdivided according to nodal status, TGFbeta1 was correlated to type-1 plasminogen activator inhibitor in the node-negative subgroup (P=0.040). Multivariate analysis revealed that, after lymph node status (P=0.0002) and urokinase-type plasminogen activator (P=0.004), TGFbeta1 was an independent prognostic marker for DFS (P=0.005) in the overall population. In the node-negative population, TGFbeta1 was the prominent prognostic factor (P=0.010). In the same population, Kaplan-Meier curves demonstrated that high TGFbeta1 level was correlated with a shorter disease-free survival (P=0.020). These data suggest that the measurement of tumoral TGFbeta1 protein level, especially for node-negative patients, might help to identify a high-risk population early in tumour progression.

Diabetes mellitus and retinopathy.

The role of somatostatin and growth hormone in eye diseases recently became a matter of interest because of its link with proliferative diabetic retinopathy. In diabetic patients the pathologic proliferation of blood vessels as a result of retinal ischemia is a major cause of blindness. The hypoxic portions of the retina release angiogenic factors, stimulating neovascularization. Somatostatin is a natural peptide hormone that affects the release of a number of other hormones, such as growth hormone, glucagon, insulin and gastrin. The somatostatin analog promises to be safe and effective treatment for severe diabetic retinopathy. This compound has been shown to block the local and systemic production of insulin-like growth factor 1 and growth hormone, which promote the angiogenesis and endothelial cell proliferation associated with proliferative retinopathy. Several studies have confirmed that using somatostatin analogs to block insulin-like growth factor 1 production is effective in reducing neovascularization and preventing disease progression to proliferative stage of diabetic retinopathy. Long-acting somatostatin analogs are currently being tested for the treatment of diabetic retinopathy. The development of somatostatin analogs with increased selectivity for receptor subtypes will provide improved outcomes in the management of patients with diabetic retinopathy.

Is medical treatment for diabetic retinopathy still an unreal dream?

Diabetic retinopathy is a highly specific vascular complication of both type 1 and type 2 diabetes, estimated to be the most frequent cause of new cases of blindness in the working population of the Western world. The prevalence of retinopathy is strongly related to the duration of diabetes and glycemic control, even though a multifactorial pathogenesis should be probably considered in genetically susceptible subjects. Intensive diabetes management, with the goal of achieving near-normal glycemia, has been shown to prevent and/or delay the onset of diabetic retinopathy and laser photocoagulation has an established clinical efficacy in preventing visual loss. However, as laser scars always destroy the retinal anatomy permanently, a medical approach to nonproliferative retinopathy should be preferred if its clinical efficacy could be demonstrated. In this paper, recently published reports supporting this hypothesis are reviewed and their conclusions critically discussed.

[The vitreous and vitreoretinal interface: natural history and associated retinal diseases]. / Il vitreo e l'interfaccia vitreoretinica: storia naturale e patologie retiniche associate.

Such significant correlations have been found between vitreal changes and retinal breaks that retinal detachment is now considered as a vitreoretinal disease. Concerning this issue, not only the posterior vitreous detachment seems to play an important role in the occurrence of rhegmatogenous retinal detachment but also the vitreoretinal interactions themself seem to be important in the pathogenesis of cystoid and diabetic macular edema, proliferative diabetic retinopathy, age-related macular degeneration, macular pucker, idiopathic macular hole and macular disease associated with optic disk pit. It seemed therefore useful to the author an updated review on alterations of the vitreoretinal interface and associated ocular diseases.

Deflazacort treatment of cystoid macular edema in patients affected by Retinitis Pigmentosa: a pilot study.

BACKGROUND: To investigate the efficacy of a long-term treatment with Deflazacort (DFZ), a third generation synthetic glucocorticoid, in patients affected by Retinitis Pigmentosa (RP) complicated by Cystoid Macular Edema (CME). METHODS: A randomized group of 10 RP subjects were selected for this pilot study and treated with DFZ for one year according to a standard protocol. Far and near Best Corrected Visual Acuity (BCVA), fluorescein angiography (Heidelberg Retina Angiograph) and computerized perimetry (Humphrey Visual Field Analyzer) were statistically assessed. RESULTS: Near visual acuities, fluorescein angiographic findings and perimetric data improved significantly (p < 0.01) while far BCVA varied only slightly (p < 0.05). No ocular or systemic side effects were recorded. CONCLUSIONS: Further case-control studies, also involving a larger number of patients, are required to confirm these preliminary results. However, the present investigation seem to suggest that DFZ could be effective in reducing fluorescein angiographic findings and improving perimetric data and near visual acuities in RP patients, even though the pathogenesis of CME remains poorly understood.

The abortive form of Bourneville-Pringle syndrome.

BACKGROUND/METHODS: To present a 26-year-old woman affected by the abortive form of Bourneville-Pringle syndrome. To our knowledge, this disease is unusual since only very few cases have been reported in the scientific literature at this time. RESULTS/CONCLUSIONS: Visual acuity was 20/20 in both eyes. No relevant ocular abnormalities were observed excepting two retinal hamartomas, a smaller one in the nasal midperiphery of the right eye and a larger one located along the super-temporal retinal vessels of the left eye. Classical signs of Bourneville-Pringle disease, such as mental retardation and epilepsy, were absent whereas a slight facial adenoma sebaceum and renal cysts represented the solely systemic manifestations of the disease. This case report confirms that retinal phakomata are a typical manifestation of Tuberous Sclerosis, even in the absence of a detected involvement of the brain.